2617 Background: Brachyury is a member of the T-box family of transcription factors which is overexpressed in several tumor types and has been associated with treatment resistance, epithelial to mesenchymal transition and metastatic potential. MVA-BN-Brachyury vaccine is a vector-based therapeutic cancer vaccine which demonstrated immunogenicity and safety in previous clinical trials. Preclinical studies suggested that IV administration of vaccines can induce superior CD8 + T-cell responses as compared with SC or IM routes. This is the first-in-human study to evaluate safety and tolerability of IV administration of this vaccine. Methods: Patients with metastatic or unresectable locally advanced malignant solid tumors were treated with MVA-BN-Brachyury vaccine in a phase 1, open-label, 3+3 dose-escalation study. Eligible patients received a total of three vaccine doses intravenously Q3W at 1x107 (DL1), 1x108 (DL2), or 1x109 infections units (Inf.U) (DL3). Patients were admitted for 48 hours for observation after each dose and had imaging at baseline and 1 and 3 months after the last vaccine dose. Primary objective was to determine the safety and tolerability and establish the recommended phase 2 dose (RP2D). Immune assays were performed in the first 10 enrolled patients. Results: In 13 patients (10 chordoma, 1 small cell breast, 1 prostate, 1 colorectal cancer), no dose-limiting toxicities were observed. Right upper quadrant abdominal pain was the only grade 3 TRAE. All other TRAEs were grade 1 or 2; most common was cytokine release syndrome (four grade 2 and one grade 1. As of Feb 2021, 9 patients completed treatment and two planned restaging scans: 5 patients had PD (3 in DL1 and 2 in DL2), 3 had SD (2 in DL2 and 1 in DL3) and 1 had PR (DL3) as their best treatment response per RECIST 1.1. One patient with advanced sacral chordoma had significant reduction of ulcerated skin metastases after 2 doses, followed by 33% shrinkage at the end of trial. Two chordoma patients with SD reported significant pain improvement. Multifunctional Brachyury, CEA, and MUC1 specific T cells were increased after vaccination in in 60%, 67%, and 50% of patients, respectively. Conclusions: MVA-BN-Brachyury IV vaccine is safe across all tested dose levels and suggesting activity in chordoma at DL3 for which this vaccine was granted FDA orphan drug designation. Mild cytokine release syndrome (rigors, chills, fever and hypotension) has been observed in 5 patients and managed with IV fluids and steroids in 2 patients. A dose 1 x 109 Inf.U (DL3) was selected for RP2D based upon available safety data. Further research is pending to evaluate clinical benefit and immunogenicity. Clinical trial information: NCT04134312.